title: Light-dependent and circadian clock-regulated activation of sterol regulatory element-binding protein, X-box-binding protein 1, and heat shock factor pathways.
abstract: The circadian clock is phase-delayed or -advanced by light when given at early or late subjective night, respectively. Despite the importance of the time-of-day-dependent phase responses to light, the underlying molecular mechanism is poorly understood. Here, we performed a comprehensive analysis of light-inducible genes in the chicken pineal gland, which consists of light-sensitive clock cells representing a prototype of the clock system. Light stimulated expression of 62 genes and 40 ESTs by >2.5-fold, among which genes responsive to the heat shock and endoplasmic reticulum stress as well as their regulatory transcription factors heat shock factor (HSF)1, HSF2, and X-box-binding protein 1 (XBP1) were strongly activated when a light pulse was given at late subjective night. In contrast, the light pulse at early subjective night caused prominent induction of E4bp4, a key regulator in the phase-delaying mechanism of the pineal clock, along with activation of a large group of cholesterol biosynthetic genes that are targets of sterol regulatory element-binding protein (SREBP) transcription factor. We found that the light pulse stimulated proteolytic formation of active SREBP-1 that, in turn, transactivated E4bp4 expression, linking SREBP with the light-input pathway of the pineal clock. As an output of light activation of cholesterol biosynthetic genes, we found light-stimulated pineal production of a neurosteroid, 7α-hydroxypregnenolone, demonstrating a unique endocrine function of the pineal gland. Intracerebroventricular injection of 7α-hydroxypregnenolone activated locomotor activities of chicks. Our study on the genome-wide gene expression analysis revealed time-of-day-dependent light activation of signaling pathways and provided molecular connection between gene expression and behavior through neurosteroid release from the pineal gland.
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Hatori
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hirota
authors.forename: Michiko
authors.initials: M
authors.lastname: Iitsuka
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kurabayashi
authors.forename: Shogo
authors.initials: S
authors.lastname: Haraguchi
authors.forename: Koichi
authors.initials: K
authors.lastname: Kokame
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Sato
authors.forename: Akira
authors.initials: A
authors.lastname: Nakai
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Tsutsui
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fukada
mesh_terms: D006907:17-alpha-Hydroxypregnenolone / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D002645:Chickens; D002784:Cholesterol / Q000096:biosynthesis; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D055106:Genome-Wide Association Study; D006360:Heat-Shock Proteins / Q000378:metabolism*; D008027:Light; D008124:Locomotion / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008297:Male; D008969:Molecular Sequence Data; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C495856:7-hydroxypregnenolone; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D000071701:Regulatory Factor X Transcription Factors; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D006907:17-alpha-Hydroxypregnenolone; D002784:Cholesterol